Thyroid hormone (T3) regulates growth and differentiation during development and modulates the activity of a wide variety of metabolic pathways in adults. Disorders that result in low (hypothyroid) or high (hyperthyroid) levels of T3 are common, and result in a multitude of clinical effects owing to the broad distribution of T3 receptors. Thyroid hormone receptors (TRs) function as transcription factors to increase or decrease levels of gene expression. Although there has been great progress in our understanding of how T3 stimulates gene transcription, the mechanism by which it turns genes off is not well- understood. The physiologic role of negative regulation by T3 is most clearly illustrated by a classical negative feedback loop in which T3 inhibits the production of pituitary thyroid-stimulating hormone (TSH). The inhibition TSH by T3 represents a critical ~set-point~ that establishes the metabolic status of an individual. In this proposal, we will continue our studies of the TSH alpha and beta genes as a model for how T3 turns off gene transcription. Recent studies have identified a family of transcriptional co-repressors and co-activators that interact with the TR. We propose that these transcriptional co- factors play a critical role in T3 mediated repression. In the case of negatively regulated genes, we hypothesize that in the absence of T3, the unliganded TR recruits co-repressors away from the promoter resulting in transcriptional activation . Upon T3 binding to the receptor, a cascade of events is proposed to culminate in T3-dependent repression. These events include the displacement of co-repressors from TR to other proteins on the target promoter, and the ability of the activated TR to bind key co-investigate the role of Nuclear Co- repressors (NcoRs) in the control of genes that are repressed in response to T3; 2) To examine the interactions of transcriptional co- factors with the CREB/CBP transcription factors as a mechanism for T3-induced repression. These studies will address a fundamental question of how T3 acts as a switch to turn off a selected array of genes. In addition to the implications for thyroid hormone action, analogous mechanisms are likely to occur for other nuclear receptors.